tbuckley/cabot-search huggingface dataset:
Not Wanting Dialysis Does Not Necessarily Mean Non-Acceptance—Words Matter
Authors: Kenneth Lempert
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article refers to:Dialysis Refusal: Discerning the Credibility of a Prior Verbal Directive Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.
Elvira Arya
Authors: Sebastian Walsh, Om Arya
Journal: BMJ (2023)

Elvira Arya (née Coelho) was born in Entebbe, Uganda, but returned to her ancestral homeland of India to complete schooling in Mangalore, south India.She originally applied to study chemistry at Mysore university, but her mother-on discovering that her grades were sufficient to study medicine-sent a telegram from Uganda, instructing her to change course.As a result, Elvira started medical school a term late and had to catch up while also acclimatising to a new culture and local language (Punjabi).This would be the first of many occasions that she would display her extraordinary intelligence, adaptability, and perseverance.After meeting her future husband, Om, at medical school, and receiving their families' blessings to marry (in itself no small feat, with her a Catholic from south India-East Africa, and him a Hindu from pre-partition northern India), she returned to Uganda.She completed medical officer jobs in Jinja and Kampala through the 1960s, punctuated by the birth of their daughter, Aruna,
A three-stage developmental pathway for human Vγ9Vδ2 T cells within the postnatal thymus
Authors: Louis Perriman, Naeimeh Tavakolinia, Sedigheh Jalali, Shuo Li, Peter F. Hickey, Daniela Amann-Zalcenstein, William Wing Ho Ho, Tracey M. Baldwin, Adam T. Piers, Igor E. Konstantinov, Jeremy Anderson, Edouard G. Stanley, Paul V. Licciardi, George Kannourakis, Shalin H. Naik, Hui-Fern Koay, Laura K. Mackay, Stuart P. Berzins, Daniel G. Pellicci
Journal: Science Immunology (2023)

Vγ9Vδ2 T cells are the largest population of γδ T cells in adults and can play important roles in providing effective immunity against cancer and infection. Many studies have suggested that peripheral Vγ9Vδ2 T cells are derived from the fetal liver and thymus and that the postnatal thymus plays little role in the development of these cells. More recent evidence suggested that these cells may also develop postnatally in the thymus. Here, we used high-dimensional flow cytometry, transcriptomic analysis, functional assays, and precursor-product experiments to define the development pathway of Vγ9Vδ2 T cells in the postnatal thymus. We identify three distinct stages of development for Vγ9Vδ2 T cells in the postnatal thymus that are defined by the progressive acquisition of functional potential and major changes in the expression of transcription factors, chemokines, and other surface markers. Furthermore, our analysis of donor-matched thymus and blood revealed that the molecular requirements for the development of functional Vγ9Vδ2 T cells are delivered predominantly by the postnatal thymus and not in the periphery. Tbet and Eomes, which are required for IFN-γ and TNFα expression, are up-regulated as Vγ9Vδ2 T cells mature in the thymus, and mature thymic Vγ9Vδ2 T cells rapidly express high levels of these cytokines after stimulation. Similarly, the postnatal thymus programs Vγ9Vδ2 T cells to express the cytolytic molecules, perforin, granzyme A, and granzyme K. This study provides a greater understanding of how Vγ9Vδ2 T cells develop in humans and may lead to opportunities to manipulate these cells to treat human diseases.
Gluten induces rapid reprogramming of natural memory αβ and γδ intraepithelial T cells to induce cytotoxicity in celiac disease
Authors: Adam Kornberg, Theo Botella, Christine S. Moon, Samhita Rao, Jared Gelbs, Liang Cheng, Jonathan Miller, Alyssa M. Bacarella, Javier A. García-Vilas, Justin Vargas, Xuechen Yu, Izabela Krupska, Erin Bush, Reuben Garcia-Carrasquillo, Benjamin Lebwohl, Suneeta Krishnareddy, Suzanne Lewis, Peter H. R. Green, Govind Bhagat, Kelley S. Yan, Arnold Han
Journal: Science Immunology (2023)

Celiac disease (CD) is an autoimmune disease in which intestinal inflammation is induced by dietary gluten. The means through which gluten-specific CD4
JHEP at a glance (August 2023)
Authors: Maria Kjaergaard, Katrine Lindvig, Katrine Holtz Thorhauge, Pere Ginés, Maja Thiele, Aleksander Krag, Michael Le, David Le, Thomas Baez, Scott Barnett, Ramsey Cheung, Mindie Nguyen, Elena Kotsiliti, Valentina Leone, Svenja Schuehle, Frank Tacke, Quentin Anstee, Mathias Heikenwalder, Mohamed El-Kassas, Mohammed Emadeldeen, Mohamed Hassany, Stephen Congly, Hongqun Liu, Samuel Lee, Kangpeng Jin, Yuze Shi, Haitian Zhang, Hua Wang, Wenjie Zhang, Beicheng Sun
Journal: Journal of Hepatology (2023)
Table of Contents
Authors: Jamie Karch, Aishwarya Raja, Henriette De, La Garza, Antonio De, Jesus Diaz Zepeda, Allen Shih, Mayra Maymone, Tania Phillips, Eric Secemsky, Neelam Vashi, Zepeda Diaz, Dirk Elston, Brett Sloan, Jonathan Kantor, Warren Heymann, Pablo Jimenez, Howard Sofen, Robert Bissonnette, Mark Lee, Joseph Fowler, David Zammit, Yusong Chen, Niranjan Rao, Louis Denis, Sandeep Gupta, Laurent Azoulay, Audray St-Jean, Matthew Dahl, Jacqueline Quail, Wusiman Aibibula, James Brophy, An-Wen Chan, Lauren Bresee, Greg Carney, Sherif Eltonsy, Hala Tamim, J Paterson, Robert Platt, Kevin Moore, Manisha Thakuria, Emily Ruiz, Gil Yosipovitch, Ahmed Awad, Robert Spencer, Catherine Munera, Fre ´de ´rique Menzaghi, Shannon Nugent, Leela Raj, Nawar Ba, Lori Latif, Janos Cory, Stephen Kovach, John Fischer, Joshua Fosnot, Ines Lin, Jeremy Etzkorn, Thuzar Shin, Cerrene Giordano, H William, Higgins Ii, Joanna Walker, Christopher Miller, Sheila Mcsweeney, Evangelos Christou, Marcus Maurer, Clive Grattan, Christos Tziotzios, John Mcgrath, Angelina Labib, Teresa Ju, Katrina Abuabara, Lawrence Eichenfield, Jonathan Silverberg, Jerry Bagel, Emma Guttman-Yassky, Diamant Thaci, Eric Simpson, John Harris, James Krueger, Daniela Myers, Amy Gamelli, Marina Milutinovic, Anne Parneix, Julie Crawford, Janet Hildebrand, Breda Munoz, Amy Paller, Jensen Yeung, Melinda Gooderham, H Chih-Ho, Charles Hong, Vimal Lynde, Perla Prajapati, Irina Lansang, Marni Turchin, Carolyn Wiseman, Michele Jack, Kerri Ramien, Parbeer Purdy, Chelsea Shope, Laura Andrews, Caroline Brailsford, Lara Lee, Amy Shen, Carol Cheng, Rhea Malik, Erica Mark, Natalia Vecerek, Nolan Maloney, Joan Leavens, Vinod Nambudiri, Art Saavedra, Marcia Hogeling, Scott Worswick, Christine Learned, Stephanie Cohen, Kaitlynne Cunningham, Sarah Alsukait, Sueheidi Santiago, Jun Lu, Marti Rothe, Anna Nichols, David Rosmarin, Jeremy Gold, Kaitlin Benedict, Shawn Lockhart, Shari Lipner, Elena Pezzolo, Alessio Gambardella, Mario Guanti, Alberto Bertoldi, Alfredo Giacchetti, Massino Donini, Giuseppe Argenziano, Luigi Naldi, Benjamin Stoff, Kate Viola, Jane Grant-Kels
Journal: Journal of the American Academy of Dermatology (2023)
Endocrine Therapy Synergizes with SMAC Mimetics to Potentiate Antigen Presentation and Tumor Regression in Hormone Receptor–Positive Breast Cancer
Authors: Francisco Hermida-Prado, Yingtian Xie, Shira Sherman, Zsuzsanna Nagy, Douglas Russo, Tara Akhshi, Zhengtao Chu, Avery Feit, Marco Campisi, Minyue Chen, Agostina Nardone, Cristina Guarducci, Klothilda Lim, Alba Font-Tello, Irene Lee, Juana García-Pedrero, Israel Cañadas, Judith Agudo, Ying Huang, Tal Sella, Qingchun Jin, Nabihah Tayob, Elizabeth A. Mittendorf, Sara M. Tolaney, Xintao Qiu, Henry Long, William F. Symmans, Jia-Ren Lin, Sandro Santagata, Isabelle Bedrosian, Denise A. Yardley, Ingrid A. Mayer, Edward T. Richardson, Giacomo Oliveira, Catherine J. Wu, Eugene F. Schuster, Mitch Dowsett, Alana L. Welm, David Barbie, Otto Metzger, Rinath Jeselsohn
Journal: Cancer Research (2023)

Abstract Immunotherapies have yet to demonstrate significant efficacy in the treatment of hormone receptor–positive (HR+) breast cancer. Given that endocrine therapy (ET) is the primary approach for treating HR+ breast cancer, we investigated the effects of ET on the tumor immune microenvironment (TME) in HR+ breast cancer. Spatial proteomics of primary HR+ breast cancer samples obtained at baseline and after ET from patients enrolled in a neoadjuvant clinical trial (NCT02764541) indicated that ET upregulated β2-microglobulin and influenced the TME in a manner that promotes enhanced immunogenicity. To gain a deeper understanding of the underlying mechanisms, the intrinsic effects of ET on cancer cells were explored, which revealed that ET plays a crucial role in facilitating the chromatin binding of RelA, a key component of the NF-κB complex. Consequently, heightened NF-κB signaling enhanced the response to interferon-gamma, leading to the upregulation of β2-microglobulin and other antigen presentation-related genes. Further, modulation of NF-κB signaling using a SMAC mimetic in conjunction with ET augmented T-cell migration and enhanced MHC-I-specific T-cell–mediated cytotoxicity. Remarkably, the combination of ET and SMAC mimetics, which also blocks prosurvival effects of NF-κB signaling through the degradation of inhibitors of apoptosis proteins, elicited tumor regression through cell autonomous mechanisms, providing additional support for their combined use in HR+ breast cancer. Significance: Adding SMAC mimetics to endocrine therapy enhances tumor regression in a cell autonomous manner while increasing tumor immunogenicity, indicating that this combination could be an effective treatment for HR+ patients with breast cancer.
Ratiometric Inclusion of Fibroblasts Promotes Both Castration‐Resistant and Androgen‐Dependent Tumorigenic Progression in Engineered Prostate Cancer Tissues
Authors: Nicole L. Habbit, Benjamin Anbiah, Joshita Suresh, Luke Anderson, Megan L. Davies, Iman Hassani, Taraswi M. Ghosh, Michael W. Greene, Balabhaskar Prabhakarpandian, Robert D. Arnold, Elizabeth A. Lipke
Journal: Advanced Healthcare Materials (2023)

Abstract To investigate the ratiometric role of fibroblasts in prostate cancer (PCa) progression, this work establishes a matrix‐inclusive, 3D engineered prostate cancer tissue (EPCaT) model that enables direct coculture of neuroendocrine‐variant castration‐resistant (CPRC‐ne) or androgen‐dependent (ADPC) PCa cells with tumor‐supporting stromal cell types. Results show that the inclusion of fibroblasts within CRPC‐ne and ADPC EPCaTs drives PCa aggression through significant matrix remodeling and increased proliferative cell populations. Interestingly, this is observed to a much greater degree in EPCaTs formed with a small number of fibroblasts relative to the number of PCa cells. Fibroblast coculture also results in ADPC behavior more similar to the aggressive CRPC‐ne condition, suggesting fibroblasts play a role in elevating PCa disease state and may contribute to the ADPC to CRPC‐ne switch. Bulk transcriptomic analyses additionally elucidate fibroblast‐driven enrichment of hallmark gene sets associated with tumorigenic progression. Finally, the EPCaT model clinical relevancy is probed through a comparison to the Cancer Genome Atlas (TCGA) PCa patient cohort; notably, similar gene set enrichment is observed between EPCaT models and the patient primary tumor transcriptome. Taken together, study results demonstrate the potential of the EPCaT model to serve as a PCa‐mimetic tool in future therapeutic development efforts.
From the July 14, 1883, Inaugural Issue of <i>JAMA</i>
Journal: JAMA (2023)

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Monoclonal Antibody and Oral Antiviral Treatment of SARS-CoV-2 Infection in US Nursing Homes
Authors: Brian E. McGarry, Benjamin D. Sommers, Andrew D. Wilcock, David C. Grabowski, Michael L. Barnett
Journal: JAMA (2023)

This study examines the use of COVID-19 antiviral treatments in US nursing homes and the facility characteristics associated with use of oral antivirals and monoclonal antibodies.
Over-the-Counter Oral Contraception as an Opportunity to Reduce Contraceptive Access Inequity
Authors: Kristyn Brandi, Krishna K. Upadhya, Stephanie B. Teal
Journal: JAMA (2023)

This Viewpoint argues that making a progestin-only contraceptive pill available for sale as an over-the-counter product will help reduce logistic barriers to safe and effective birth control.
Radiographic Absence of the Left Humeral Head
Authors: Adam D. Roche, Orla C. Sheehan
Journal: JAMA (2023)

An older patient with history of surgical decompression for syringomyelia, poor mobility, and frequent falls presented with pain, numbness, and paresthesias in his left upper extremity. Radiograph showed complete absence of the left humeral head. What is the diagnosis, and what would you do next?
Lifestyle Enrichment in Later Life and Its Association With Dementia Risk
Authors: Zimu Wu, Danushika H. Pandigama, Jo Wrigglesworth, Alice Owen, Robyn L. Woods, Trevor T.-J. Chong, Suzanne G. Orchard, Raj C. Shah, Kerry M. Sheets, John J. McNeil, Anne M. Murray, Joanne Ryan
Journal: JAMA Network Open (2023)

Importance Lifestyles enriched with socially and mentally stimulating activities in older age may help build cognitive reserve and reduce dementia risk. Objective To investigate the association of leisure activities and social networks with dementia risk among older individuals. Design, Setting, and Participants This longitudinal prospective cohort study used population-based data from the ASPREE Longitudinal Study of Older Persons (ALSOP) for March 1, 2010, to November 30, 2020. Community-dwelling individuals in Australia aged 70 years or older who were generally healthy and without major cognitive impairment at enrollment were recruited to the ALSOP study between March 1, 2010, and December 31, 2014. Data were analyzed from December 1, 2022, to March 31, 2023. Exposures A total of 19 measures of leisure activities and social networks assessed at baseline were classified using exploratory factor analysis. Main Outcomes and Measures Dementia was adjudicated by an international expert panel according to Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria. Cox proportional hazards regression examined dementia risk over 10 years, adjusting for education, socioeconomic status, and a range of health-related factors. Results This study included 10 318 participants. Their median age was 73.8 (IQR, 71.6-77.2) years at baseline, more than half (52.6%) were women, and most self-identified as White (98.0%). In adusted analyses, more frequent engagement in adult literacy activities (eg, writing letters or journaling, using a computer, and taking education classes) and in active mental activities (eg, playing games, cards, or chess and doing crosswords or puzzles) was associated with an 11.0% (adjusted hazard ratio [AHR], 0.89 [95% CI, 0.85-0.93]) and a 9.0% (AHR, 0.91 [95% CI, 0.87-0.95]) lower risk of dementia, respectively. To a lesser extent, engagement in creative artistic activities (craftwork, woodwork, or metalwork and painting or drawing) (AHR, 0.93 [95% CI, 0.88-0.99]) and in passive mental activities (reading books, newspapers, or magazines; watching television; and listening to music or the radio) (AHR, 0.93 [95% CI, 0.86-0.99]) was also associated with reduced dementia risk. In contrast, interpersonal networks, social activities, and external outings were not associated with dementia risk in this sample. Conclusions and Relevance These results suggest that engagement in adult literacy, creative art, and active and passive mental activities may help reduce dementia risk in late life. In addition, these findings may guide policies for geriatric care and interventions targeting dementia prevention for older adults.
HLA-I Evolutionary Divergence Confers Response to PD-1 Blockade plus Chemotherapy in Untreated Advanced Non–Small Cell Lung Cancer
Authors: Tao Jiang, Qiqi Jin, Jiahao Wang, Fengying Wu, Jian Chen, Gongyan Chen, Yunchao Huang, Jianhua Chen, Ying Cheng, QiMing Wang, Yueyin Pan, Jianying Zhou, Jianhua Shi, Xingxiang Xu, LiZhu Lin, Wei Zhang, Yiping Zhang, Yunpeng Liu, Yong Fang, Jifeng Feng, Zhehai Wang, Sheng Hu, Jian Fang, Yongqian Shu, Jiuwei Cui, Yi Hu, Wenxiu Yao, Xingya Li, Xiaoyan Lin, Rui Wang, Yongsheng Wang, Wei Shi, Gaohua Feng, Jun Ni, Beibei Mao, Dandan Ren, Huaibo Sun, Henghui Zhang, Luonan Chen, Caicun Zhou, Shengxiang Ren
Journal: Clinical Cancer Research (2023)

Abstract Purpose: PD-1 blockade plus chemotherapy has become the new standard of care in patients with untreated advanced non–small cell lung cancer (NSCLC), whereas predictive biomarkers remain undetermined. Experimental Design: We integrated clinical, genomic, and survival data of 427 NSCLC patients treated with first-line PD-1 blockade plus chemotherapy or chemotherapy from two phase III trials (CameL and CameL-sq) and investigated the predictive and prognostic value of HLA class I evolutionary divergence (HED). Results: High HED could predict significantly improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in those who received PD-1 blockade plus chemotherapy [in the CameL trial, ORR: 81.8% vs. 53.2%; P = 0.032; PFS: hazard ratio (HR), 0.47; P = 0.012; OS: HR, 0.40; P = 0.014; in the CameL-sq trial, ORR: 89.2% vs. 62.3%; P = 0.007; PFS: HR, 0.49; P = 0.005; OS: HR, 0.38; P = 0.002], but not chemotherapy. In multivariate analysis adjusted for PD-L1 expression and tumor mutation burden, high HED was independently associated with markedly better ORR, PFS, and OS in both trials. Moreover, the joint utility of HED and PD-L1 expression showed better performance than either alone in predicting treatment benefit from PD-1 blockade plus chemotherapy. Single-cell RNA sequencing of 58,977 cells collected from 11 patients revealed that tumors with high HED had improved antigen presentation and T cell–mediated antitumor immunity, indicating an inflamed tumor microenvironment phenotype. Conclusions: These findings suggest that high HED could portend survival benefit in advanced NSCLC treated with first-line PD-1 blockade plus chemotherapy. See related commentary by Dimou, p. 4706
Poor Outcome in Postpartum Breast Cancer Patients Is Associated with Distinct Molecular and Immunologic Features
Authors: Hanne Lefrère, Kat Moore, Giuseppe Floris, Joyce Sanders, Iris M. Seignette, Tycho Bismeijer, Dennis Peters, Annegien Broeks, Erik Hooijberg, Kristel Van Calsteren, Patrick Neven, Ellen Warner, Fedro Alessandro Peccatori, Sibylle Loibl, Charlotte Maggen, Sileny N. Han, Katarzyna J. Jerzak, Daniela Annibali, Diether Lambrechts, Karin E. de Visser, Lodewyk Wessels, Liesbeth Lenaerts, Frédéric Amant
Journal: Clinical Cancer Research (2023)

Patients with postpartum breast cancer diagnosed after cessation of breastfeeding (postweaning, PP-BCPW) have a particularly poor prognosis compared with patients diagnosed during lactation (PP-BCDL), or to pregnant (Pr-BC) and nulliparous (NP-BC) patients, regardless of standard prognostic characteristics. Animal studies point to a role of the involution process in stimulation of tumor growth in the mammary gland. However, in women, the molecular mechanisms that underlie this poor prognosis of patients with PP-BCPW remain vastly underexplored, due to of lack of adequate patient numbers and outcome data.We explored whether distinct prognostic features, common to all breast cancer molecular subtypes, exist in postpartum tumor tissue. Using detailed breastfeeding data, we delineated the postweaning period in PP-BC as a surrogate for mammary gland involution and performed whole transcriptome sequencing, immunohistochemical, and (multiplex) immunofluorescent analyses on tumor tissue of patients with PP-BCPW, PP-BCDL, Pr-BC, and NP-BC.We found that patients with PP-BCPW having a low expression level of an immunoglobulin gene signature, but high infiltration of plasma B cells, have an increased risk for metastasis and death. Although PP-BCPW tumor tissue was also characterized by an increase in CD8+ cytotoxic T cells and reduced distance among these cell types, these parameters were not associated with differential clinical outcomes among groups.These data point to the importance of plasma B cells in the postweaning mammary tumor microenvironment regarding the poor prognosis of PP-BCPW patients. Future prospective and in-depth research needs to further explore the role of B-cell immunobiology in this specific group of young patients with breast cancer.
Maternal Hepatitis B Virus Infection and Pregnancy Outcomes of Freeze-Thaw Embryo Transfer
Authors: Ling-Ling Ruan, Ming-Xing Chen, Enoch Appiah Adu-Gyamfi, Li-Hong Geng, Li-Juan Fu, Qi Wan, Yu-Bin Ding
Journal: JAMA Network Open (2023)

This cohort study assesses the association of maternal hepatitis B virus (HBV) serostatus with pregnancy outcomes in women undergoing freeze-thaw embryo transfer (FET).
The Z-nucleic acid sensor ZBP1 in health and disease
Authors: Jonathan Maelfait, Jan Rehwinkel
Journal: The Journal of Experimental Medicine (2023)

Nucleic acid sensing is a central process in the immune system, with far-reaching roles in antiviral defense, autoinflammation, and cancer. Z-DNA binding protein 1 (ZBP1) is a sensor for double-stranded DNA and RNA helices in the unusual left-handed Z conformation termed Z-DNA and Z-RNA. Recent research established ZBP1 as a key upstream regulator of cell death and proinflammatory signaling. Recognition of Z-DNA/RNA by ZBP1 promotes host resistance to viral infection but can also drive detrimental autoinflammation. Additionally, ZBP1 has interesting roles in cancer and other disease settings and is emerging as an attractive target for therapy.